Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D249/14—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
  • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
  • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
  • C07D285/01—Five-membered rings
  • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
  • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
  • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention relates to new alkanol derivatives which have a highly selective action on histamine-H 2 receptors, processes for their preparation and pharmaceutical preparations containing these compounds, and the use of these compounds in therapy.
• Cimetidine and ranitidine have already been used therapeutically as anti-ulcerative agents. Both these substances, however, have a relatively short half life and are therefore required to be administered in several daily doses of tablets with dose units of 160 to 300 mg in a therapeutically determined form. There is therefore a need for anti-ulcerative agents which have a more prolonged action and/or higher activity than cimetidine or ranitidine.
• the H 2 antagonistic action can also be demonstrated on waking Heidenhain-Pouch dogs by the method of Black et al, "Nature", 236, 385 (1971) and waking fistulized cats. These compounds also antagonize the histamine action on the frequency of contraction of the isolated right atrium of the guinea-pig but have no effect on histamine induced contractions of isolated, smooth gastrointestinal muscle when these are produced by H 2 antagonists.
• substances which inhibit histamine-H 2 receptors have an inhibitory action both on the basal gastric acid secretion and on the gastric acid secretion induced by gastrine, histamine, methacholine or food, they may be used for the treatment of peptic ulcers caused by excessive gastric acid secretion and in the treatment of hyperacidic gastritis.
• the present invention thus relates to new alkanol derivatives corresponding to the general formula I
• R 1 and R 2 which may be identical or different, denote hydrogen, C 1-10 -alkyl, preferably C 1-3 -alkyl (lower alkyl), C 5-6 -cycloalkyl such as cyclopentyl or cyclohexyl, amino or lower alkylamino such as methyl, ethyl or propylamino when m has the value 1.
• R 1 and R 2 together form the group (NH 2 ) 2 CH ⁇ .
• R 1 and R 2 may also, together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocyclic ring which may be unsubstituted or substituted with a methyl group.
• rings examples include the pyrrolidine, methylpyrrolidine, morpholine, thiomorpholine, piperidine, methylpiperidine, N-methylpiperazine, homopiperidine, heptamethyleneimino and octamethyleneimino ring, the pyrrolidine and piperidine ring being preferred.
• Q denotes a furan, thiophene, thiazole or benzene ring.
• the furan ring is preferably inserted in the molecule in the 2,5-position.
• the thiophene ring is preferably inserted in the 2,5- or 2,4-position and the thiazole ring is preferably inserted in the 2,4-position.
• the benzene ring is preferably inserted by bonds in the 1- and 3- or 1- and 4-position.
• the benzene ring is preferred among these structural units, a benzene ring incorporated in the 1- and 3-position being particularly preferred.
• X represents a sulphur or oxygen atom or the group --CHOH.
• Y denotes a single bond or the group --CHOH.
• the symbol n may assume the value 1 or 2.
• R 3 represents one of the following groups: ##STR2##
• R 4 represents a hydrogen atom, a C 1-3 -alkyl group (lower alkyl group) or a propargyl group
• R 5 represents a hydrogen atom or a C 1-3 -alkyl group (lower alkyl group).
• m preferably has the value 1 and R 1 is preferably a hydrogen atom.
• R 1 is a C 1-10 -alkyl group, in particular a C 1-3 -alkyl group, and R 2 is a C 5-6 -cycloalkyl group.
• R 1 and R 2 represent methyl and/or ethyl or R 1 and R 2 together with the nitrogen atom to which they are attached represent a substituted or unsubstituted 5-membered or 6-membered alicyclic heterocyclic ring, a pyrrolidine, methylpyrrolidine, morpholine, thiomorpholine, piperidine, methylpiperidine, N-methylpiperazine, homopiperidine, heptamethyleneimino or octamethyleneimino ring, in particular a pyrrolidine or piperidine ring.
• a particularly preferred group of compounds according to the invention is characterised in that R 1 and R 2 together with the nitrogen atom to which they are attached represent a substituted or unsubstituted 5- to 8-membered alicyclic heterocyclic ring is described above, in particular a pyrrolidine or piperidine ring.
• R 1 and R 2 and m have the meanings indicated above
• Q represents a benzene ring which is inserted in the remainder of the molecule by attachment in the 1- and 3- or 1- and 4-position, preferably in the 1- and 3-position
• X represents the group --CHOH
• Y represents a single bond
• n 1 or 2
• R 3 represents the groups indicated in claim 1 as described above.
• R 1 , R 2 , m, Q, X, Y and n have the meanings indicated above and R 6 represents the group ##STR5## wherein L 1 denotes a methoxy, ethoxy or butoxy group as exit group is reacted in a solvent with an amine corresponding to the general formula III
• R 4 represents a hydrogen atom, a methyl group or a propargyl group, to form the compound according to the invention corresponding to the general formula I.
• the reaction is carried out in a solvent, for example in an alcohol such as methanol, ethanol or isopropanol, preferably ethanol.
• the compound corresponding to the general formula II and the amine corresponding to the general formula III are preferably used in equimolar quantities.
• the reaction temperature may range from room temperature to the reflux temperature.
• the reaction product is worked up and isolated in the usual manner.
• the compound obtained is optionally converted into a physiologically acceptable salt thereof.
• R 1 , R 2 , m, Q, X, Y and n have the meanings indicated above and R 7 represents ##STR7## wherein L 2 denotes a thiomethyl, methoxy, ethoxy or phenoxy group as exit group
• the reaction is preferably carried out in a solvent such as an alcohol, e.g. methanol, ethanol or isopropanol, preferably ethanol.
• the reactants may, for example, be used in equimolar quantities.
• the reaction temperature may range from room temperature to the reflux temperature of the solvent used.
• the reaction product is worked up and isolated in the usual manner.
• the compound obtained is optionally converted into a physiologically acceptable salt thereof.
• R 1 , R 2 , m,, Q, X, Y and n have the meanings indicated above
• a compound corresponding to formula VI ##STR9## is reacted with a compound corresponding to formula VI ##STR9## to form a compound according to the invention corresponding to the general formula I.
• This reaction is also preferably carried out in a solvent, for example, in an alcohol such as methanol, ethanol or isopropanol, preferably ethanol, and using equimolar quantities of reactants.
• the reaction temperature may range from room temperature to the reflux temperature of the solvent.
• the compound of formula VI used in this reaction is known and has been described, for example, in J. Org. Chem. 48, 763 (1983).
• the reaction product is worked up and isolated in the usual manner.
• the compound obtained is optionally converted into a physiologically acceptable salt thereof.
• the reaction may be carried out at a temperature ranging from room temperature to the reflux temperature of the solvent used and it may be carried out, for example, using equimolar quantities.
• the reaction product is worked up and isolated in the usual manner.
• the compound obtained is optionally converted into a physiologically acceptable salt thereof.
• the invention also covers the various stereochemical forms (enantiomers) of the compounds of formula I and their physiologically acceptable hydrates and salts with inorganic and organic acids.
• These salts may be formed, for example, with mineral acids such as hydrochloric, hydrobromic or hydriodic acid, phosphoric acid, metaphosphoric acid, nitric acid or sulphuric acid or with organic acids such as formic acid, acetic acid, propionic acid, phenylacetic acid, tartaric acid, citric acid, fumaric acid, methanesulphonic acid, etc.
• the compounds according to the invention may be incorporated in any desired formulations for administration.
• the invention therefore also covers pharmaceutical preparations containing at least one compound according to the invention for use in human or veterinary medicine.
• Such medicaments may be prepared by the conventional methods using one or more pharmaceutically acceptable excipients or diluents.
• the compounds according to the invention may therefore be formulated for oral, buccal, local, parenteral or rectal administration, oral administration being preferred.
• the medicament may be provided, for example, in the form of tablets, capsules, powders, solutions, syrups or suspensions prepared by the conventional methods using acceptable diluents.
• the medicaments may be provided in the form of tablets or sachets formulated in the usual manner.
• the compounds according to the invention may also be made up into preparations for parenteral administration by bolus injection or continuous infusion.
• Formulations for injection may be prepared as ampoules of unit doses or as multiple dose containers with added preservatives.
• the medicaments may assume forms such as suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulating auxiliaries such as stabilizers and/or dispersing agents.
• the active ingredients may also be presented in powder form to be reconstituted with a suitable carrier such as sterile, pyrogen-free water before use.
• the compounds according to the invention may also be made up into preparations for rectal administration, such as suppositories or retention enemas containing, for example, the usual suppository excipients such as cocoa butter or other glycerides.
• the compounds according to the invention may be incorporated in the usual formulations for ointments, creams, gels, lotions, powders or sprays.
• a suitable daily dose of compounds according to the invention consist of 1 to 4 doses amounting to a total of 5 mg to 1 g/day, preferably 5 to 250 mg/day, depending on the patient's condition.
• the compounds according to the invention are distinguished by their improved pharmacological activity. This is demonstrated by the results of the pharmaceutical comparison tests described below.
• the aqueous phase is separated and extracted with 25 ml of methylene chloride.
• the combined organic phases are dehydrated with sodium sulphate and concentrated by evaporation to yield a yellow resin which is chromatographed with methylene chloride/methanol (9:1) against silica gel. After concentration by evaporation, the second fraction yields the title compound as a pale yellow oil.
• Example 1 c 0.52 g (76%) of the title compound are obtained by a method analogous to that of Example 1 c,d from 0.47 g (1.9 mmol) of 1-amino-3-[3-(1-piperidylmethyl)phenyl]-2-propanol and 0.36 g (1.9 mmol) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide after chromatography against silica gel, using methanol/conc. ammonia (95:5) as eluent.
• a mixture of 6.84 g (20 mmol) of 5-(1-piperidylmethyl)-2-S-isothiourea-methylthiophene-dihydrochloride and 6.1 g (30 mmol) of N-(2,3-epoxypropyl)-phthalimide is introduced into 50 ml of ethanol, and a solution of 2.4 g (60 mmol) of NaOH in 60 ml of ethanol is slowly added at 0° to 5° C. The mixture is then left to react for one hour at 0° to 5° C. and 3 hours at room temperature.
• the compound is prepared by a method analogous to that of Example 1 c,d from 1.5 g (5 mmol) of 2-hydroxy-3-[5-(1-piperidylmethyl)-2-thienylthio]propylamine in 10 ml of ethanol and 0.95 g (5 mmol) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide.
• the compound is prepared by a method analogous to that of Example 8 a from 5-(dimethylaminomethyl)-2-S-isothiourea-methylfuran-bis-maleate and N-(2,3-epoxypropyl)phthalimide.
• the method of preparation is analogous to that of Example 8 b.
• the compound is prepared by a method analogous to that of Example 8 a from [2-(guanidinothiazol-4-yl)methyl]-S-isothiourea-dihydrochloride and N-(2,3-epoxypropyl)-phthalimide.
• the method of preparation is analogous to that of Example 8 b.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Indole Compounds (AREA)
• Heterocyclic Compounds Containing Sulfur Atoms (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
• Furan Compounds (AREA)
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• 1984
  • 1984-02-10 DE DE19843404786 patent/DE3404786A1/de not_active Withdrawn
  • 1984-12-27 EP EP84116345A patent/EP0154721A1/de not_active Withdrawn
• 1985
  • 1985-01-22 US US06/693,204 patent/US4659721A/en not_active Expired - Fee Related
  • 1985-02-07 HU HU85471A patent/HUT37772A/hu unknown
  • 1985-02-08 JP JP60023374A patent/JPS60188352A/ja active Pending

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